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Abstract:

An array 1 with microprotrusions comprises a base 2 and tapered
microprotrusions 3 each disposed on the base 2 and tapering down toward
the tip from the bottom. Letting a distance from the tip to the bottom on
an arbitrary side of each microprotrusion 3 as a and letting the length
of a second line segment prepared by projecting a first line segment
representing the distance a onto the base 2 as b, a relationship of
1.0<(a/b)≦7.5 holds.

Claims:

1. An array with microprotrusions, comprising: a base; and tapered
microprotrusions each disposed on the base and tapering down toward the
tip from the bottom connected to the base, wherein letting a distance
from the tip to the bottom on an arbitrary side of each of the
microprotrusions as a and letting the length of a second line segment
prepared by projecting a first line segment representing the distance
onto the base as b, a relationship of 1.0<(a/b)≦7.5 holds.

2. An array with microprotrusions, comprising: a base; and
microprotrusions, wherein the microprotrusions stretch the skin by 1.01
to 3.0 times.

3. The array with microprotrusions according to claim 1, wherein the
microprotrusions are made of polylactic acid.

4. The array with microprotrusions according to claim 1, wherein the
height of the microprotrusions is 20 to 400 μm, and the width of the
bottom is 10 to 200 μm.

5. The array with microprotrusions according to claim 1, wherein the
density of the microprotrusions is 100 to 10000 protrusions/cm.sup.2.

6. The array with microprotrusions according to claim 1, wherein the tip
is flat, and the area of the tip is 20 to 600 μm.sup.2.

7. The array with microprotrusions according to claim 1, wherein the tip
is rounded, and the radius of curvature of the tip is 2 to 100 μm.

8. The array with microprotrusions according to claim 1, wherein the tip
is pointed, and the apical angle of the tip projected onto an arbitrary
reference surface orthogonal to the base is 16 degrees or larger.

9. The array with microprotrusions according to claim 1, wherein the
microprotrusions do not penetrate the stratum corneum of the skin.

Description:

DESCRIPTION

[0001] 1. Technical Field

[0002] An embodiment of the present invention relates to an array with
microprotrusions for administering an active ingredient via the skin.

[0003] 2. Background Art

[0004] Heretofore, one in which microprotrusions are disposed on a base
(array with microprotrusions) has been known as an array for improving
the transdermal absorption of drugs. The microprotrusions are aimed at
puncturing the stratum corneum, which is the outermost layer of the skin,
and various sizes or shapes have been proposed (see Patent Literature 1).

[0005] Moreover, various methods have also been proposed as to methods for
applying drugs in the case of using the array with microprotrusions. In
Patent Literature 2, it is described that: a drug is coated onto the
surfaces of the microprotrusions; grooves or hollow portions for
permeating a drug or a biogenic substance are disposed in the
microprotrusions; a drug is mixed with the microprotrusions themselves;
etc. Moreover, in Patent Literature 2, it is preferred that a reservoir
medium should contain sugars, and it is also described that the reservoir
medium particularly contains sugars for stabilization that forms glass
(amorphous solid substance), such as lactose, raffmose, trehalose, or
sucrose.

[0006] Furthermore, in Patent Literatures 3 and 4, there is the
description that by setting the height of the microprotrusions to 10
μm to 3 mm and setting the shape of the tips of the microprotrusions
to a flat shape or a rounded shape, the microprotrusions can administer
cosmetics, pharmaceuticals, or compounds such as plastics attached to or
contained in the protrusions while stretching the epidermis without
penetrating the stratum corneum.

CITATION LIST

Patent Literature

[0007] Patent Literature 1: JP 2001-506904

[0008] Patent Literature 2:
JP 2004-504120

[0009] Patent Literature 3: JP 2007-089792

[0010] Patent
Literature 4: JP 2007-130417

SUMMARY OF INVENTION

Technical Problem

[0011] In the case of administering an active ingredient to a sensitive
portion in the skin, it is preferred not to completely penetrate the
stratum corneum, in order to avoid the possibility that the skin gets
damaged. The reason therefor is that when a through-hole is formed in the
stratum corneum, the occurrence of skin irritation (erythema) or
reduction in the water-holding capacity of the skin resulting from
increase in water loss from the skin is caused. However, the patterns of
shapes or heights of protrusions in the transdermal administration
apparatus described in Patent Literatures 3 and 4 above are enormous, and
it is not said to disclose the optimum array.

[0012] Thus, an array with microprotrusions has been demanded, which is
capable of administering an active ingredient to the skin without pain
and with reliability while preventing damage to the stratum corneum of
the skin.

Solution to Problem

[0013] During the course of diligent study to solve the problems described
above, the present inventors have found that merely setting the shape and
density of microprotrusions may result in perforation of the corneum, and
it is important to consider the extent to which the skin stretches.

[0014] Specifically, an array with microprotrusions according to an
embodiment of the present invention comprises: a base; and tapered
microprotrusions each disposed on the base and tapering down toward the
tip from the bottom connected to the base, wherein letting a distance
from the tip to the bottom on an arbitrary side of each of the
microprotrusions as a and letting the length of a second line segment
prepared by projecting a first line segment representing the distance
onto the base as b, a relationship of 1.0<(a/b)≦7.5 holds.

[0015] According to such an array with microprotrusions, the skin at a
site coming into contact with each protrusion when the microprotrusion is
placed thereagainst stretches by a value of a/b described above at the
maximum. In this context, the value a/b represents the rate of stretching
provided that the skin has been stretched completely along the side of
the microprotrusion, and can be said to be the maximum rate of stretching
of the skin by the microprotrusion. The present inventors have found that
if this maximum rate of stretching can be kept at 7.5 or less, there is
no risk of penetrating the stratum corneum of the skin. Specifically, by
determining the shape of the microprotrusion so as to satisfy a
relationship of 1.0<(a/b)≦7.5, an active ingredient can be
administered to the skin without pain and with reliability via the
stratum corneum that has thinned out by stretching, with damage to the
stratum corneum prevented.

[0016] An array with microprotrusions according to another embodiment of
the present invention comprises: a base; and microprotrusions, wherein
the microprotrusions stretch the skin by 1.01 to 3.0 times. According to
such an array with microprotrusions, since the rate of stretching of the
skin can be kept at 1.01 to 3.0, an active ingredient can be administered
to the skin without pain and with reliability via the stratum corneum
that has thinned out by stretching, with damage to the stratum corneum
prevented.

[0017] In the array with microprotrusions according to a further
alternative embodiment, the microprotrusions may be made of polylactic
acid. Since the polylactic acid is biodegradable, in this case, burdens
on the skin, etc., can be reduced even if the microprotrusions remain on
the skin by breaking or the like. Moreover, the polylactic acid is also
advantageous in terms of antigenicity and the unit price of a material.

[0018] In the array with microprotrusions according to a further
alternative embodiment, the height of the microprotrusions may be 20 to
400 μm, and the width of the bottom may be 10 to 200 μm.

[0019] In the array with microprotrusions according to a further
alternative embodiment, the density of the microprotrusions may be 100 to
10000 protrusions/cm2.

[0020] In the array with microprotrusions according to a further
alternative embodiment, the tip may be flat, and the area of the tip may
be 20 to 600 μm2. In this case, since pressure against the skin
contacted with the tip of the microprotrusion is reduced, damage to this
site can be avoided more reliably.

[0021] In the array with microprotrusions according to a further
alternative embodiment, the tip may be rounded, and the radius of
curvature of the tip may be 2 to 100 μm. In this case, since pressure
against the skin contacted with the tip of the microprotrusion is
reduced, damage to this site can be avoided more reliably.

[0022] In the array with microprotrusions according to a further
alternative embodiment, the tip may be pointed, and the apical angle of
the tip projected onto an arbitrary reference surface orthogonal to the
base may be 16 degrees or larger. Since the value a/b can thereby be
within the range of 1.0<(a/b)≦7.5, an active ingredient can be
administered to the skin without pain and with reliability, with damage
to the stratum corneum prevented even if the microprotrusions are
pointed.

[0023] In the array with microprotrusions according to a further
alternative embodiment, the microprotrusions may not penetrate the
stratum corneum of the skin.

Advantageous Effects of Invention

[0024] According to an aspect of the present invention, letting a distance
from the tip to the bottom on a side of each microprotrusion as a and
letting the length of a second line segment prepared by projecting a
first line segment representing the distance onto the base as b, a
relationship of 1.0<(a/b)≦7.5 holds. By thus determining the
shape of the microprotrusion, an active ingredient can be administered to
the skin without pain and with reliability, with damage to the stratum
corneum of the skin prevented.

BRIEF DESCRIPTION OF DRAWINGS

[0025] FIG. 1 is a perspective view showing one example of an array with
microprotrusions according to an embodiment.

[0026]FIG. 2 is a sectional view taken along the II-II line in FIG. 1.

[0027]FIG. 3(a) is a perspective view of a conical microprotrusion; FIG.
3(b) is a sectional view taken along the B-B line in FIG. 3(a); FIG. 3(c)
is a perspective view of a quadrangular pyramidal microprotrusion; and
FIG. 3(d) is a sectional view taken along the D-D line in FIG. 3(c).

[0030]FIG. 6 is a diagram schematically showing the state in which the
skin has been stretched incompletely along the microprotrusion.

DESCRIPTION OF EMBODIMENTS

[0031] Hereinafter, embodiments of the present invention will be described
in detail with reference to the accompanying drawings. Incidentally, in
the description of the drawings, the same reference signs will be used to
designate the same or similar components, so that the description will be
omitted.

[0032] First, the constitution of an array 1 with microprotrusions
(hereinafter, also simply referred to as an "array 1") according to an
embodiment will be described. In the present specification, the "array"
is merely the name of an instrument. FIG. 1 is a perspective view showing
one example of the array 1 according to an embodiment. FIG. 2 is a
sectional view taken along the II-II line in FIG. 1. FIG. 3 is a
perspective view and a sectional view of a microprotrusion 3.

[0033] As shown in FIG. 1, the array 1 comprises a base 2 and a plurality
of microprotrusions 3 arranged in a two-dimensional pattern on the base
2.

[0034] The base 2 is a foundation for supporting the microprotrusions 3.
In the base 2, a plurality of through-holes 4 are formed so as to be
arranged in a two-dimensional pattern. The microprotrusions 3 and the
through-holes 4 are alternately arranged in the diagonal direction of the
base 2. By means of the through-holes 4, it becomes possible to
administer a biologically active ingredient from the back of the base 2.
As a matter of course, a base free from such through-holes may be used.
The area of the base 2 may be 0.5 cm2 to 300 cm2, may be 1
cm2 to 100 cm2, or may be 1 cm2 to 50 cm2. A base of
the desired size may be constituted by connecting several individuals of
this base 2.

[0035] Each microprotrusion 3 is a microstructure, and its height (length)
h is, for example, 20 to 400 gm. In this context, the reason why the
length of the microprotrusion 3 is set to 20 μm or larger is that the
transdermal administration of an active ingredient is secured, and the
reason for setting to 400 gm or smaller is that the microprotrusion is
prevented more reliably from piercing the corneum of the skin.
Alternatively, if the length of the microprotrusion 3 is 300 gm or
smaller, an active ingredient in an amount that should enter
intradermally can be administered efficiently. The length of the
microprotrusion 3 may be 50 to 300 μm.

[0036] In this context, the microprotrusion is a tapered structure
tapering down toward the tip from the bottom connected to the base 2 and
means a needle shape in a broad sense or a structure containing a needle
shape. As a matter of course, the microprotrusion is not limited to the
needle shape having a sharp tip and also includes a shape free from a
pointed end. In the case where the microprotrusion 3 has a conical
structure, the diameter at its base may be on the order of 5 to 250 μm
or may be 10 to 200 μm. Although conical microprotrusions 3 are shown
in FIG. 1, microprotrusions in a polygonal pyramidal shape such as a
quadrangular pyramidal shape may be used.

[0037] Letting a distance from the tip to the bottom on a side (along a
side) of the microprotrusion 3 as a and letting the length of a line
segment prepared by projecting a line segment representing the distance a
onto the base 2 as b, the relationship represented by the following
formula (1) may hold:

1.0<(a/b)≦7.5 (1)

[0038] As an example, the case where the microprotrusion 3 is
conical/quadrangular pyramidal is shown in FIG. 3. In the case where the
microprotrusion 3 is conical as shown in FIG. 3(a), a line segment
representing a distance a from a tip P to the bottom on its side is an
oblique side PQ in a triangle PQR (sectional view including the tip P) of
FIG. 3(b). Moreover, a line segment prepared by projecting the oblique
side PQ onto the base 2 along a direction orthogonal to the base 2 is a
line segment QM in the triangle PQR. In this context, a point M is the
foot of a perpendicular from the point P to the base QR. Even if the
microprotrusion 3 is quadrangular pyramidal as shown in FIG. 3(c), the
same as in the conical case can hold true therefor as shown in FIG. 3(d).

[0039] In this context, the value a/b is the rate of stretching provided
that the skin in a normal state has been stretched completely along the
side of the microprotrusion 3, i.e., an index representing by what times
the skin is stretched by the microprotrusion 3 at the maximum, and can be
said to be the maximum rate of stretching of the skin by the
microprotrusion 3. In the examples of FIG. 3, the maximum rate of
stretching of the skin may satisfy the above formula (1) in the case
where the skin at a site along the line segment QM has been stretched
along the oblique side PQ by the placement of the array 1 (contact of the
array 1) thereagainst. This is because if the rate of stretching of the
skin is kept at this level, damage to the stratum corneum can be avoided
more reliably when the array 1 is placed thereagainst. The rate of
stretching may be 1.01 to 3.0 or may be 1.01 to 2.0.

[0040] In the case where the microprotrusion 3 is conical or pyramidal,
the apical angle a (see FIGS. 3(c) and 3(d)) of the tip projected onto an
arbitrary reference surface orthogonal to the base 2 may be 16 degrees or
larger (less than 180 degrees). Specifically, the minimum value of the
apical angle a of the tip projected onto the arbitrary reference surface
may be 16 degrees or larger. Since the maximum rate of stretching of the
skin can be kept within the range of the above formula (1) by thus
adjusting the apical angle, damage attributed to the microprotrusion can
be avoided more reliably.

[0041] The above formula (1) holds not only for the examples of FIG. 3,
but also holds even if the microprotrusion is arbitrarily pyramidal or is
arbitrarily oblique conical. However, it is required that the formula (1)
should hold for an arbitrary side if the microprotrusion is pyramidal and
that the formula (1) should hold for an arbitrary generatrix if conical.

[0042] The microprotrusion may not be conical and pyramidal, and, for
example, the tip may be flat or may be rounded. In the case where the tip
is flat, the area of the flat portion may be 20 to 600 μm2 or may
be 50 to 250 μm2. Alternatively, in the case where the tip is
rounded, the radius of curvature of the tip may be 2 to 100 μm or may
be 5 to 30 μm. Even if the microprotrusion has such a shape, the above
formula (1) holds. Since pressure against the skin contacted with the tip
of the microprotrusion is reduced by thus processing the tip of the
microprotrusion, damage to this site can be avoided more reliably.

[0043] Although the microprotrusions 3 do not penetrate the stratum
corneum of the skin in usual use, it is also possible that some
microprotrusions 3 penetrate the stratum corneum as long as there is no
inconvenience such as inflammation from the viewpoint of skin beauty.
Specifically, the epidermis thins out by stretching by the
microprotrusions 3, and an active ingredient permeates the epidermis that
has been rendered permeable, though it is possible that a portion of the
active ingredient enters into the skin from the pierced corneum.

[0044] Regarding the density of the microprotrusions 3, typically, spacing
is given so that a density of approximately 1 to 10 per mm is provided as
to the row of needles. In general, adjacent rows are spaced from each
other by a distance substantially equal to the space between the needles
in each row, and have a density of 100 to 10000 needles per cm2. The
density of the microprotrusions 3 may be 200 to 5000 protrusions or may
be 300 to 2000 protrusions or 400 to 850 protrusions.

[0045] Examples of the material of the base 2 or the microprotrusions 3
include silicon, silicon dioxide, ceramics, metals (stainless, titanium,
nickel, molybdenum, chromium, cobalt, etc.), and synthetic or natural
resin materials, but include biodegradable polymers such as polylactic
acid, polyglycolide, polylactic acid-co-polyglycolide, pullulan,
caprolactone, polyurethane, and polyanhydrides, and synthetic or natural
resin materials such as polycarbonate, polymethacrylic acid, ethylene
vinyl acetate, polytetrafluoroethylene, and polyoxymethylene, which are
non-degradable polymers, in consideration of the antigenicity of the
microprotrusions and the unit price of the material. Moreover, hyaluronic
acid, sodium hyaluronate, pullulan, dextran, dextrin or chondroitin
sulfate, a cellulose derivative, and the like, which are polysaccharides
may be used.

[0046] The material of the microprotrusions 3 may be a biodegradable resin
such as polylactic acid in consideration of breaking on the skin.

[0047] Although a polylactic acid homopolymer of poly-L-lactic acid or
poly-D-lactic acid, a poly-L/D-lactic acid copolymer, and a mixture
thereof, etc. are included in the polylactic acid, any of these may be
used. Moreover, the larger the average molecular weight of the polylactic
acid becomes, the larger its strength becomes, and those of 40,000 to
100,000 can be used.

[0048] Examples of the method for producing the base 2 or the
microprotrusions 3 include wet etching or dry etching using a silicon
base, precision machining using metal or resin (electro-discharge
machining, laser processing, grinding, hot embossing, injection molding,
etc.), and machinery cutting. By these processing methods, the
protrusions and the supporting portion are integrally molded. Examples of
the method for rendering the protrusions hollow include a method of
performing secondary processing by laser processing or the like after
preparation of the protrusions.

[0049] Coating 5 with an active ingredient is provided on the base 2
and/or the microprotrusions 3. In the present embodiment, the coating 5
is one in which a coating solution containing a polymer carrier having
compatibility with the active ingredient is anchored to a portion or the
whole of the microprotrusions 3 and/or surface of the base 2. Examples of
the polymer carrier include carboxyvinyl polymers and polyethylene oxide
described later, polyvinylpyrrolidone, polyvinyl alcohol, and cellulose
derivatives. "Anchored" refers to maintaining the state in which the
coating solution is almost evenly attached to an object. Immediately
after coating, the coating solution is anchored in a dry state by a known
drying method of air drying, vacuum drying, freeze drying, or a
combination thereof, but is not limited to anchoring in a dry state
because of also retaining a water content in equilibrium with a
surrounding atmosphere, an organic solvent, or the like after transdermal
administration.

[0051] The content of the coating carrier in the coating agent may be 0.1
to 70% by weight. Moreover, the coating carrier may be viscous to some
extent so as not to drip.

[0052] A liquid composition used for coating the base 2 and/or the
microprotrusions 3 is prepared by mixing a biocompatible carrier, a
beneficial active ingredient to be delivered, and, in some cases, any
coating auxiliary with a volatile liquid. The volatile liquid can be
water, dimethyl sulfoxide, dimethylformamide, ethanol, isopropyl alcohol,
and a mixture thereof. For example, water may be selected. The liquid
coating solution or suspension can typically have 0.1 to 65% by weight of
a beneficial biologically active ingredient concentration, and the
concentration may be 1 to 40% by weight or 10 to 30% by weight. The
coating may become an anchored state. A surfactant may be zwitterionic,
amphoteric, cationic, anionic, or nonionic. For example, Tween 20 and
Tween 80, other sorbitan derivatives, for example, sorbitan laurate, and
alkoxylated alcohols, for example, laureth-4, may be used. For example,
the addition of a surfactant is also effective for dissolving a larger
amount of the active ingredient in the coating carrier.

[0056] The peptides, the polypeptides, and the proteins as the active
ingredient that may be used in the present embodiment include, for
example, polymers having a long chain whose number of carbon atoms is at
least approximately 10, and a high molecular weight of, for example, at
least 1000, and they are formed by the self-condensation of amino acids.
Examples of such proteins include: collagen; deoxyribonuclease; iodized
corn protein; keratin; milk protein; protease; serum protein; silk; sweet
almond protein; wheat germ protein; wheat protein; alpha and beta helix
of wheat protein or keratin protein; and hair proteins such as
intermediate filament protein, high-sulfur content protein,
ultrahigh-sulfur content protein, intermediate filament-associated
protein, high-tyrosine protein, high-glycine/tyrosine protein,
trichohyalin, and mixtures thereof.

[0059] Examples of the antimicrobial agents that may be used in the
present embodiment include bacitracin, erythromycin, neomycin,
tetracycline, chlortetracycline, benzethonium chloride, phenol, and
mixtures thereof.

[0060] Examples of the skin softeners and the skin moisturizers that may
be used in the present embodiment include mineral oils, lanolin,
vegetable oils, isostearyl isostearate, glyceryl laurate, methyl
gluceth-10, methyl gluceth-20, chitosan, and mixtures thereof.

[0061] Examples of the hair conditioners that may be used in the present
embodiment include not only lipophilic compounds such as cetyl alcohol,
stearyl alcohol, hydrogenated polydecene, and mixtures thereof, but also
quaternary compounds such as behenamidopropyl PG-dimonium chloride,
tricetyl ammonium chloride, dihydrogenated tallowamidoethyl
hydroxyethylmonium methosulfate, and mixtures thereof.

[0063] Examples of the skin-whitening agents that may be used in the
present embodiment include hydroquinone and its derivatives, catechol and
its derivatives, ascorbic acid and its derivatives, ellagic acid and its
derivatives, kojic acid and its derivatives, tranexamic acid and its
derivatives, resorcinol derivatives, placenta extracts, arbutin,
oil-soluble licorice extracts, and mixtures thereof.

[0066] Examples of the bactericides and the disinfectants that may be used
in the present embodiment include thimerosal, phenol, thymol,
benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone
iodine, cetylpyridinium chloride, eugenol, and trimethylammonium bromide.
Examples of the vasoconstrictors that may be used together with the patch
of the present embodiment include naphazoline nitrate, tetrahydrozoline
hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride,
and tramazoline hydrochloride. Examples of the hemostats that may be used
together with the patch of the present embodiment include thrombin,
phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid,
carbazochrome, carbazochrome sodium sulfonate, rutin, and hesperidin.

[0067] Examples of the chemotherapeutic drugs that may be used in the
present embodiment include sulfamine, sulfathiazole, sulfadiazine,
homosulfamine, sulfisoxazole, sulfisomidine, sulfamethizole, and
nitrofurazone. Examples of the antibiotics that may be used together with
the patch of the present embodiment include penicillin, methicillin,
oxacilline, cephalothin, cephalodine, erythromycin, lincomycin,
tetracycline, chlorotetracycline, oxytetracycline, methacycline,
chloramphenicol, kanamycin, streptomycin, gentamycin, bacitracin, and
cycloserine.

[0068] Examples of the antiviral drugs that may be used in the present
embodiment include protease inhibitors, thymidine kinase inhibitors,
sugar or glycoprotein synthesis inhibitors, constituent protein synthesis
inhibitors, adherence and adsorption inhibitors, and nucleoside analogs
such as acyclovir, penciclovir, valaciclovir, and ganciclovir.

[0071] The vitamin C used in the present embodiment promotes collagen
(connective tissue) synthesis, lipid (fat) and carbohydrate metabolism,
and neurotransmitter synthesis. The vitamin C is also essential for the
optimum maintenance of the immune system. The vitamin C is harmful to a
wide range of cancer cells, particularly, melanoma. Tyrosine oxidase,
which catalyzes the aerobic activity of tyrosine that is converted to
melanin and other pigments, is also prevented in the presence of vitamin
C from being activated. The vitamin C has been found to be effective for
catalyzing immune response to infections with many viruses and bacteria.
In addition to many applications described above, the vitamin C is
essential for collagen synthesis and trauma treatment. The patch to which
the present embodiment is applied may contain a combination of vitamin C,
vitamin E, and other ingredients such as humectants, collagen synthesis
promoters, and facial scrubs.

[0073] These active ingredients may be used alone or may be used in
combination of two or more types, and as a matter of course, active
ingredients in any form of inorganic salts or organic salts are also
included as long as they are pharmaceutically acceptable salts. Moreover,
although the active ingredient is basically incorporated in the coating
carrier, the active ingredient can also be supplied later via the
through-holes 4 formed in the base 2 without being incorporated in the
coating carrier. Alternatively, the active ingredient is directly applied
to the skin, and then, the array 1 with microprotrusions can also be
placed against the same site on the skin. In this case, it becomes
possible to promote the permeation of the active ingredient into the skin
by virtue of the effect of stretching the skin and the effect of ODT
(occlusive dressing therapy) on the skin.

[0074] An auxiliary instrument for fixing the array 1 may be used in
administration using the array 1. However, direct administration by hand
pressing is more preferable than, for example, an array that generates
high collision energy as described in JP 2004-510535. When the array 1
comes in contact with the skin, administration is performed with a force
of 1.0 to 10 kg or administration is performed with a force of 1.0 to 7
kg or with a force of 1.0 to 4 kg. Moreover, the administration time with
this force is not so long and is on the order of a few seconds to 120
minutes at the longest. The administration time may be within 60 minutes
or may be within 15 minutes. In some cases, instantaneous administration
for less than 1 second is also possible. However, it is also possible to
continue to administer the active ingredient by then fixing the array to
the skin.

EXAMPLES

[0075] Hereinafter, Examples of a device with microprotrusions will be
described specifically, and however, the constitution of the device with
microprotrusions is not limited to Examples below.

Example 1

Primary Rabbit Skin Irritation Test

<Operational Procedure>

[0076] Three types of arrays with microprotrusions made of polylactic acid
in which the lengths of the protrusions differed (h: 70 μm, 110 μm,
and 150 μm), and an array consisting only of a base were used. With
regard to three types of arrays with microprotrusions, all the shapes of
the protrusions were quadrangular pyramids, and all the densities of the
protrusions were 841 protrusions/cm2. A test substance was pressed
for 5 seconds with a force of 3 kg against the skin in the shaved dorsal
portion of each 18-week-old female Japanese white rabbit (Kbl:JW) and
then applied for 2 hours (with a covering member) (the number of
individuals n=6). Then, the test substance was peeled off after 2 hours
from administration, and erythema/eschar and edema formation were grossly
observed on 0.5, 2, 24, 48, and 72 hours after peeling and graded on the
basis of the scoring criteria of Draize et al. (Table 1).

[0077] The assessment of primary skin irritation was performed by
calculating a primary irritation index (P.I.I.) and using the scoring
criteria of Draize (Table 2) shown below. The primary irritation index
was calculated by respectively determining the average scores of each
individual as to erythema and edema formation after 0.5 hours and 24
hours after test substance (MN) peeling, further determining the total
sum of the average scores of each group, and dividing by the number of
individuals.

[0078] As shown in Table 3, the primary irritation index (P.1.1) of the
skin was 0.0 for all of three types of arrays with the respective
microprotrusions (70 μm, 110 μm, and 150 μm) and the array with
only a base.

[0079] An array with microprotrusions made of polylactic acid in which the
length of the protrusions was 150 μm was used. In this array, the
shape of the protrusions was a quadrangular pyramid, and the density of
the protrusions was 841 protrusions/cm2. Similarly to Example 1
above, the array was pressed against the rabbit skin and applied for 2
hours, and then, occult blood reaction was assayed (the number of
individuals n=6). Judgment criteria for occult blood were judged through
color reaction when 20 μL of saline was added dropwise to the
application site immediately after removing the array (MN) and test paper
was placed thereagainst. Pretest II (urine occult blood test paper,
manufactured by Wako Pure Chemical Industries, Ltd.) was used as a test
paper for assay. The skin was abraded using an 18-G needle as a positive
control and tested similarly.

[0080] The occult blood reaction of the protrusion-applied group was
observed in none of the rabbits, and the occult blood reaction was
negative. On the other hand, with regard to the abraded group, evident
coloring (blue) was observed with the test paper, though bleeding was
hardly observed grossly. Since the occult blood reaction was not observed
as to the microprotrusions of 150 μm in height, it was expected that
the occult blood reaction was not observed as to the microprotrusions of
150 μm or smaller in height used in the irritation test.

[0081] Three types of arrays with microprotrusions made of polylactic acid
in which the lengths of the protrusions differed (h: 70 μm, 110 μm,
and 150 μm), and an array consisting only of a base were used. With
regard to three types of arrays with microprotrusions, all the shapes of
the protrusions were quadrangular pyramids, and all the densities of the
protrusions were 841 protrusions/cm2. Similarly to Example 1 above,
each array was applied by pressing against the rabbit skin, and water
loss was assayed around 2 hours after application. Transepidermal water
loss (TEWL) is an index for assaying the barrier function of the skin,
and it has been shown that water loss from a damaged site increases when
the barrier structure of the stratum corneum gets damaged.

[0082] The assay of transepidermal water loss was conducted before
application of the array and after a few minutes from peeling and
performed using VapoMeter (manufactured by Dlefin). An array with
microprotrusions of 500 μm in height with a similar shape was used for
a positive control group, and an array consisting only of a base was used
for a negative control group.

[0083] The experimental results are shown in FIG. 4. In the case of using
the array with microprotrusions of 500 μm in height, an evident rise
in water loss was confirmed. On the other hand, although slight increase
in water loss was observed for the arrays with microprotrusions of 70 to
150 μm in height, it was shown that the microprotrusions did not have
influence on water loss because a similar rising tendency was also
observed for the array not provided with microprotrusions.

[0084] From these results shown in FIG. 4, it was assumed that the arrays
with microprotrusions of 70 to 150 μm in height did not give physical
damage to the skin under this condition.

Example 4

Excised Human Skin Impedance Assay

<Operational Procedure>

[0085] Three types of arrays with microprotrusions made of polylactic acid
in which the lengths of the protrusions differed (h: 70 μm, 110 μm,
and 150 μm), and an array consisting only of a base were used. All the
shapes of the protrusions were quadrangular pyramids, and all the
densities of the protrusions were 841 protrusions/cm2. Each array
was pressed for 5 seconds at a pressure of 3 kg against excised human
skin, and the impedance value of the skin was measured before and after
pressing. The impedance value of the skin is an index representing the
barrier function of the skin as in TEWL, and it has been shown that the
impedance value decreases when the skin gets damaged.

[0086] The measurement of the skin impedance value was performed by
placing a skin fragment (skin thickness: approximately 500 μm, 5
cm×5 cm) onto a stainless base, placing a round nonwoven fabric of
φ14 in diameter impregnated with saline and a silver electrode of
φ12 in diameter onto the base application site, and connecting the
stainless base and the silver electrode with an LCR meter (3522-50, Hioki
E.E. Corp.) (measurement conditions: 1V, 10 Hz). An array with
microprotrusions of 500 μm in height with a similar shape was used for
a positive control group, and an array consisting only of a base was used
for a negative control group.

[0087] The experimental results are shown in FIG. 5. In the case of using
the array with microprotrusions of 500 μm in height, the tendency that
the impedance value decreased after pressing was observed. On the other
hand, in the arrays with microprotrusions of 70 to 150 μm in height,
correlation was not observed between the rate of decrease and the height,
though a slight decreasing tendency was observed.

Rate of Stretching of Skin in Examples 2 to 4

<Case Where Skin was Stretched Completely Along Side of
Microprotrusion>

[0088] This case will be described using FIGS. 3(c) and 3(d). In the case
where the skin with the length b along the line segment QM in a normal
state has been stretched to the length a completely along the line
segment PQ, the rate of stretching thereof depends on the apical angle a
of the microprotrusion 3, regardless of the length of the microprotrusion
3. As shown in Tables 5 to 7 below, the rates of stretching in the case
where the apical angles α were 16, 18, and 20 degrees were 7.19,
6.37, and 5.74, respectively.

[0089] <Case Where Skin was Stretched Incompletely Along Side of
Microprotrusion>

[0090] This case will be described using FIG. 6. FIG. 6 schematically
shows the situation in which a portion of the skin was contacted with the
base surface 2a between adjacent microprotrusions 3 by the pressing of
the array with microprotrusions, so that the skin was not stretched along
the side of the microprotrusion 3. If the skin is contacted with the base
surface 2a at a midpoint Q' between the microprotrusions 3, the skin with
a length b' along a line segment Q'M in a normal state shall be stretched
to a length a' along a line segment PQ'. The rate a'/b' of stretching of
the skin becomes a value shown in Table 8 below according to the height
of the microprotrusions 3 provided that the microprotrusions 3 are
arranged with equal spacing of 350 μm and the apical angle of the
microprotrusions 3 is 20 degrees.

[0091] In an aspect of the present invention, since an active ingredient
intended for beauty can be administered to the skin without pain and with
reliability, with damage to the stratum corneum of the skin prevented,
the convenience of the array with microprotrusions is drastically
enhanced, and thus, there is industrial applicability.